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Why do some primate malarias relapse? Nicholas J. White1,2,* Relapse may have evolved in malaria as a mechanism to avoid suppression by more virulent species in mixed infections, thereby increasing transmission opportunities. Later evolution of long latency in Plasmodium vivax was a necessary adaptation as early hominins moved to colder areas with shorter mosquito breeding seasons. Genetic diversity was maintained through heterologous hypnozoite activation. Sleeping Parasites Sporozoan (apicomplexan) parasites have developed many different mechanisms to facilitate persistence in their hosts. Plasmodial parasites persist through continuous multiplication in blood for extended periods. In several of the primate malarias an alternative strategy has evolved. Some of the sporozoites persist as sleeping forms or ‘hypnozoites’, which lie dormant in the liver hepatocytes for long periods after inoculation and wake weeks or months after inoculation [1]. These relapses have a remarkable periodicity [2]. In humans, Plasmodium vivax is the main cause of relapsing malaria. There are an estimated 100[5_TD$IF]–400 million cases each year mainly in Asia, Oceania, the horn of Africa and South America. P. vivax is much more difficult than Plasmodium falciparum to eliminate, largely because of relapses which are a major contributor to morbidity. But why do P. vivax, Plasmodium ovale and some other primate malarias relapse? What evolutionary pressure led to this remarkable adaptation? I propose that it arose in these [6_TD$IF]primate parasites as an adaptive ‘defensive’ response to
concomitant symptomatic[7_TD$IF] infections with together [6,7]. In higher transmission setvirulent parasites such as Plasmodium tings there is cross-species regulation of falciparum[1_TD$IF] or other[2_TD$IF] now extinct[3_TD$IF] species. parasite densities [7]. Through a range of different epidemiological circumstances, Epidemiology and Early Evolution the two malaria parasites are effectively Premunition to P. vivax develops more in competition. Under similar conditions rapidly than to P. falciparum [3]. This is of competition the relapse mechanism largely because of frequent relapse–a sin- evolved in the predecessors of today's gle inoculation giving rise to multiple epi- primate plasmodial parasites. sodes of illness in the case of P. vivax but only one in the case of P. falciparum. Intrahost Competition Before the era of modern medicine, this In contrast with P. falciparum, P. vivax difference would presumably have been gametocytogenesis occurs immediately, smaller, as primary infections of either so the infection is transmissible as soon species would have persisted in the blood as it reaches densities in blood that are for weeks or months, unless challenged sufficient for gametocyte ingestion by by superinfection. In all epidemiological feeding anopheline mosquitos. But as contexts, relapse is an important contrib- sexual parasites are derived from asexual utor to P. vivax incidence and prevalence. parasites, anything that suppresses asexIn tropical regions, relapse intervals are ual multiplication reduces overall transmisshort and frequent. The first relapse para- sibility of the infection. Transmissibility is sites begin to emerge from the liver greatest during higher-density infections approximately [8_TD$IF]4 weeks after sporozoite which generate larger numbers of gameinoculation ([9_TD$IF]2 weeks after the primary ill- tocytes. Competition with the predecesness) and reach patency (detectable para- sor of P. falciparum (or other more virulent sitaemias) approximately [10_TD$IF]1 week later [2]. parasites, such as the parasite which The infection becomes transmissible just drove Duffy negativity to fixation in much before this. In temperate regions, where of Africa) in human primate ancestors promosquito breeding seasons are short and vided an evolutionary selection pressure P. vivax is obliged to overwinter in on other malaria parasites to avoid suphumans, the intervals to first relapse are pression in the acute phase of mixed much longer [2]. Adaptation to temperate malaria infections. climes would have occurred later as hominins ventured further north from the tropi- During the acute phase of the infection, cal areas [1_TD$IF]long [12_TD$IF]after the evolution of the before the acquisition of disease controlrelapse mechanism. ling immunity, nonspecific host defence mechanisms comprising fever, proinflamIf P. vivax emerged as a primate malaria matory cytokine release, and splenic actiparasite in the forests of Africa, then it vation contain the infection in most cases. would always have had to contend with As a byproduct this limits the expansion of more virulent, more rapidly developing, any concomitant infection. Although P. and generally dominant malaria parasites vivax is a more potent inducer of this with which it shared mosquito vectors and host-defence response than P. falcipaprimate hosts. When P. falciparum and P. rum, we know from the simultaneous vivax are inoculated together, then P. fal- inoculation experiments in human volunciparum usually dominates [4,5]; it devel- teers and malaria therapy that P. falcipaops more rapidly in the liver and then the rum usually predominates [4–6]. Thus P. symptomatic blood stage infection sup- vivax gets hit in the crossfire and retreats. presses asexual multiplication of P. vivax. But once the acute illness has subsided Despite this, there is a remarkably high there is less impediment to P. vivax multirate of mixed infections with the two spe- plication. In many tropical areas, the first cies, so both are commonly transmitted relapse coincides with a decline in
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P. falciparum parasitaemia in untreated infections, as antibodies to the predominant P. falciparum PfEMP1 variant expressed at the surface of the red blood cell rise [8]. P. vivax also has gene families suggesting antigenic variation, and can also persist in the blood for protracted periods in nonimmune individuals, although how it does so is not well understood. However, it seems likely that persistence of a blood stage infection of P. vivax at the densities necessary for transmission would result in a significant immune response and, without antigenic variation, clearance of the infection. Disappearance from the blood without providing an ‘immunizing dose’ of infection, under suppression from P. falciparum (or its evolutionary precursor) and reappearance weeks or months later is a much more efficient strategy to generate transmissible densities of sexual parasites. In a mixed infection, the acute illness associated with falciparum malaria suppresses the concomitant blood stages of P. vivax reducing their densities and thus transmissibility. The illness also delays or prevents development of any developing P. vivax liver stage parasites by reducing the availability of iron through increases in hepcidin (the main hormone regulating iron availability) [9]. As sporozoite inocula are generally thought to be small (median six to ten sporozoites), these two factors reduce the transmission potential of sporozoites that activate immediately after arrival to the liver. Delaying activation until the nonspecific host responses have attenuated or abated would increase the probability of generating and maintaining transmissible parasite densities. This is ‘place betting’. Through this mechanism, P. vivax can establish and transmit if there is no coinfection, or retreat and transmit later if there is. It also increases the probability that minor populations in mixed genotype P. vivax infections can transmit. Even if a heterologous genotype is outcompeted in the primary infection, while it has hypnozoites in the liver, it still has a chance to transmit every time it
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relapses. With multiple rolls of the dice, the probability of successful transmission increases. Relapse therefore makes most efficient use of the inoculated sporozoites to optimize the probability of transmission.
Evolutionary Advantages of Relapse Systemic febrile illness (such as falciparum or vivax malaria) may activate relapses [2,10]. This links infections of different species and provides a highly effective mechanism for ensuring genetic recombination between unrelated P. vivax parasites in times or places where transmission is low. Nonspecific activation by febrile illness or another stimulus may result in the simultaneous development of hypnozoites from the same (homologous) and earlier (heterologous) inoculations. In anopheline vectors feeding during the ensuing blood stage infection, male and female gametes derived from the different inoculations can mate (heterologous recombination) creating genetic diversity [2,11]. This maximizes the opportunities for both transmission (even if there is homologous strain immunity) and immune evasion, and it explains how P. vivax maintains high genetic diversity even in areas of very low seasonal transmission. The evolutionary advantage of P. vivax linking to P. falciparum, whilst avoiding it during the acute phase, may be to exploit transmission conditions optimally. A symptomatic P. falciparum infection is unequivocal evidence of the recent availability of vector mosquitoes. For a sleeping hypnozoite, the optimal time to wake is when[13_TD$IF] vector mosquitos are abundant but the fire of P. falciparum acute illness has subsided, so that effective P. vivax multiplication is unhindered. If the illness associated with relapse is sufficiently severe, this will activate further hypnozoites creating regular periodicity (every [14_TD$IF]3 weeks approximately). Illness is a sign of inadequate immunity, and that translates into an increased probability that the subsequent relapse can reach patency. When immunity to P. falciparum is acquired more slowly than to
P. vivax, as in many low-transmission settings, then falciparum malaria in adults may wake P. vivax hypnozoites that would not be woken by asymptomatic vivax malaria. As early man moved north to areas where winter temperatures were inhospitable to mosquitos and fell below those allowing sporogony, there was less competition from P. falciparum, but there were also fewer opportunities for relapse activation in the short summer transmission season. Early relapse became a wasted transmission opportunity, and a clock evolved so that the relapse came to coincide with next year's anopheline vector abundance. Notably, second relapses were at [14_TD$IF]3-week intervals as in the tropical strains. Eventually, further north, with even shorter transmission seasons, the opportunity to transmit from the primary illness diminished, and nearly all the inoculated sporozoites became dormant hypnozoites [2,12]. Long-latency P. vivax had become long-incubation-period P. vivax (hibernans). 1 Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand 2 Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom
*Correspondence:
[email protected] (N.J. White). http://dx.doi.org/10.1016/j.pt.2016.08.014 References 1. Garnham, P.C.C. (1967) Relapses and latency in malaria. Protozoology 2, 55–64 2. White, N.J. (2011) Determinants of relapse periodicity in Plasmodium vivax malaria. Malar. J. 10, e297 3. Luxemburger, C. et al. (1996) The epidemiology of malaria in a Karen population on the western border of Thailand. Trans. R. Soc. Trop. Med. Hyg. 90, 105–111 4. Boyd, M.F. and Kitchen, S.F. (1937) Simultaneous inoculation with Plasmodium vivax and P. falciparum. Am. J. Trop. Med. 17, 855–861 5. Mayne, B. and Young, M.D. (1938) Antagonism between species of malaria parasites in induced mixed infections. Public Health Rep. 53, 1289–1291 6. Mayxay, M. et al. (2004) Mixed-species malaria infections in humans. Trends Parasitol. 20, 233–240 7. Bruce, M.C. and Day, K.P. (2003) Cross-species regulation of Plasmodium parasitemia in semi-immune children from Papua New Guinea. Trends Parasitol. 19, 271–277 8. Recker, M. et al. (2011) Antigenic variation in Plasmodium falciparum malaria involves a highly structured switching pattern. PLoS Pathog. 7, e1001306
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9. Portugal, S. et al. (2011) Host-mediated regulation of superinfection in malaria. Nat. Med. 17, 732–737 10. Shanks, G.D. and White, N.J. (2013) The activation of vivax malaria hypnozoites by infectious diseases. Lancet Infect. Dis. 13, 900–906
11. Noviyanti, R. et al. (2015) Contrasting transmission dynamics of co-endemic Plasmodium vivax and P. falciparum: implications for malaria control and elimination. PLoS Negl. Trop. Dis. 9, e0003739
12. Battle, K.E. et al. (2014) Geographical variation in Plasmodium vivax relapse. Malar. J. 13, 144
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